Plaque clearance is a better correlate of neural protection via passive amyloid immunization than soluble amyloid-beta (Aβ) clearance, and this protection is based on Fc receptor-mediated Aβ phagocytosis. These are the conclusions reported in the February 3 online PNAS, by Frederique Bard and colleagues at Elan Pharmaceuticals in South San Francisco, California, after a comparison of various Aβ antibody isotypes and their affinities for different epitopes of Aβ.
In the aftermath of Elan’s halted vaccination trial, these and other researchers have taken a step back to try to understand how Aβ pathology interacts with the immune system, and also to determine if passive immunization with antibodies to Aβ could become a safe and effective alternative to active immunization with Aβ peptide (see related ARF discussion and ARF related news story). In the present study, the researchers first compared antibodies directed against various epitopes of the Aβ1-42 peptide. They found that only antibodies that bind the N-terminal region were effective in binding plaques in unfixed brain tissue from PDAPP transgenic mouse brain or in triggering plaque clearance by phagocytosis in an ex-vivo assay (see ARF related news story and ARF related news story. Similar results were found in vivo. The authors report that plaque-binding correlated with clearance and neural protection, whereas the affinity of antibodies for soluble Aβ correlated less well with these measures of efficacy.
They also report that the isotype of the antibodies determined its efficacy in plaque clearance and neuronal protection; IgG2a antibodies were more effective than IgG1 or IgG2b. IgG2a has a much higher affinity for the phagocytic Fc receptors, and the authors conclude that antibody efficacy is primarily mediated by Fc receptors and not by complement system receptors.—Hakon Heimer
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- Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8. PubMed.